To test genetic pleiotropy,the main difficulty lies in the failure to find a test statistic and calculate its p-value for determining whether to reject the null hypothesis or not.To deal with this issue,the authors pr...To test genetic pleiotropy,the main difficulty lies in the failure to find a test statistic and calculate its p-value for determining whether to reject the null hypothesis or not.To deal with this issue,the authors propose a quasi p-value,which plays the similar role as the usual p-value in genetic pleiotropy test.In the formula of the quasi p-value,the main task is to determine the weights.In this paper,the authors present two weighted methods based on the Bayesian rule and extend the proposed methods to study a single binary trait using a data-driven EM algorithm.Extensive simulation studies are conducted for the assessment of the two proposed methods and illustrate that the proposed methods improve the performance of power by comparing with the two-stage method.In addition,the authors apply the proposed methods to the data of tropical storms that occurred on the mainland of China since 1949,investigating the relationship between the landing site and predictive features of tropical storms,and showing that the landing site has a large influence on at least two features of typhoon.展开更多
We reviewed the study by He et al,which investigates the genetic correlation between ulcerative colitis(UC)and anxiety using bidirectional Mendelian rando-mization.This study reveals a genetic link between UC and anxi...We reviewed the study by He et al,which investigates the genetic correlation between ulcerative colitis(UC)and anxiety using bidirectional Mendelian rando-mization.This study reveals a genetic link between UC and anxiety,diverging from prior research associating higher anxiety with Crohn’s disease.While the study's use of large-scale genome-wide association studies data is commendable,it faces limitations such as single nucleotide polymorphism selection biases,lack of multiple testing corrections,and a reliance on European populations.Future research should address these limitations,incorporate diverse populations,and explore psychotherapeutic interventions to improve UC management and patient outcomes.展开更多
Marker-assisted selection(MAS)and genomic selection(GS)breeding have greatly improved the efficiency of rice breeding.Due to the influences of epistasis and gene pleiotropy,ensuring the actual breeding effect of MAS a...Marker-assisted selection(MAS)and genomic selection(GS)breeding have greatly improved the efficiency of rice breeding.Due to the influences of epistasis and gene pleiotropy,ensuring the actual breeding effect of MAS and GS is still a difficult challenge to overcome.In this study,113 indica rice varieties(V)and their 565 testcross hybrids(TC)were used as the materials to investigate the genetic basis of 12 quality traits and nine agronomic traits.The original traits and general combining ability of the parents,as well as the original traits and midparent heterosis of TC,were subjected to genome-wide association analysis.In total,381 primary significantly associated loci(SAL)and 1,759 secondary SALs that had epistatic interactions with these primary SALs were detected.Among these loci,322 candidate genes located within or nearby the SALs were screened,204 of which were cloned genes.A total of 39 MAS molecular modules that are beneficial for trait improvement were identified by pyramiding the superior haplotypes of candidate genes and desirable epistatic alleles of the secondary SALs.All the SALs were used to construct genetic networks,in which 91 pleiotropic loci were investigated.Additionally,we estimated the accuracy of genomic prediction in the parent V and TC by incorporating either no SALs,primary SALs,secondary SALs or epistatic effect SALs as covariates.Although the prediction accuracies of the four models were generally not significantly different in the TC dataset,the incorporation of primary SALs,secondary SALs,and epistatic effect SALs significantly improved the prediction accuracies of 5(26%),3(16%),and 11(58%)traits in the V dataset,respectively.These results suggested that SALs and epistatic effect SALs identified based on an additive genotype can provide considerable predictive power for the parental lines.They also provide insights into the genetic basis of complex traits and valuable information for molecular breeding in rice.展开更多
Control of flowering time is crucial for reproductive success of cereal crops, and has a significant impact on grain yield as well as adaptation to diverse environmental conditions.Plants integrate signals from both e...Control of flowering time is crucial for reproductive success of cereal crops, and has a significant impact on grain yield as well as adaptation to diverse environmental conditions.Plants integrate signals from both environmental cues and endogenous regulatory pathways to fine-tune flowering time. The CCT domain originally described to a 43-amino acid sequence at the C-terminus of three Arabidopsis proteins, namely CONSTANS(CO),CO-LIKE, and TIMING OF CAB1(TOC1). The CCT domain-containing genes(CCT genes),which encode transcription co-factors, are the major genetic determinants that modulate flowering time, and this in turn enables plants to effectively expand their territory to take advantage of favorable habitats. Moreover, certain CCT genes have pleiotropic effects on morphological traits and confer resistance/tolerance to biotic/abiotic stresses. CCT genes can be classified into three families, namely COL(CONSTANS-like), PRR(Pseudo-response regulator), and CMF(CCT motif family),based on their non-CCT domains. During domestication, natural and artificial selection resulted in reduced nucleotide diversity of CCT genes in modern cultivated cereals than their wild types. Here, we review the features and functions of CCT genes in cereal crops and propose future research to focus on CCT genes and their utilization in crop breeding.展开更多
Genetic factors play an important role in the etiology of inflammatory bowel disease(IBD). The launch of genome-wide association study(GWAS) represents a landmark in the genetic study of human complex disease. Concurr...Genetic factors play an important role in the etiology of inflammatory bowel disease(IBD). The launch of genome-wide association study(GWAS) represents a landmark in the genetic study of human complex disease. Concurrently, computational methods have undergone rapid development during the past a few years, which led to the identification of numerous disease susceptibility loci. IBD is one of the successful examples of GWAS and related analyses. A total of 163 genetic loci and multiple signaling pathways have been identified to be associated with IBD. Pleiotropic effects were found for many of these loci; and risk prediction models were built based on a broad spectrum of genetic variants. Important gene-gene, gene-environment interactions and key contributions of gut microbiome are being discovered. Here we will review the different types of analyses that have been applied to IBD genetic study, discuss the computational methods for each type of analysis, and summarize the discoveries made in IBD research with the application of these methods.展开更多
Cascade speciation and reinforcement can evolve rapidly when traits are pleiotropic and act as both signal/cue in nonrandom mating. Here, we examine the contribution of two key traits-assortative mating and self-ferti...Cascade speciation and reinforcement can evolve rapidly when traits are pleiotropic and act as both signal/cue in nonrandom mating. Here, we examine the contribution of two key traits-assortative mating and self-fertilization--to reinforcement and （by extension） cascade speciation. First, using a population genetic model of reinforcement we find that both assortative mating and self-fertilization can make independent contributions to increased reproductive isolation, consistent with reinforcement. Self-fertilization primarily evolves due to its 2-fold transmission advantage when inbreeding depression （d） is lower （d〈 0.45） but evolves as a function of the cost of hybridization under higher inbreeding depression （0.45 〈 d〈 0.48）. When both traits can evolve simultaneously, increased self-fertilization often prohibits the evolution of assortative mating. We infer that, under specific conditions, mating system transitions are more likely to lead to increased reproductive isolation and initiate cascade speciation, than assortative mating. Based on the results of our simulations, we hypothesized that transitions to self-fertilization could contribute to clade-wide diversification if reinforcement or cascade speciation is common. We tested this hypothesis with comparative data from two different groups. Consistent with our hypothesis, there was a trend towards uniparental reproduction being associated with increased diversification rate in the Nematode phylum. For the plant genus Mimulus, however, self-fertilization was associated with reduced diversification. Reinforcement driving speciation via transitions to self-fertilization might be short lived or unsustainable across macroevolutionary scales in some systems （some plants）, but not others （such as nematodes）, potentially due to differences in susceptibility to inbreeding depression and/or the ability to transition between reproductive modes.展开更多
It is generally accepted that taxa exhibit genetic variation in phenotypic plasticity, but many questions remain unan- swered about how divergent plastic responses evolve under dissimilar ecological conditions. Hormon...It is generally accepted that taxa exhibit genetic variation in phenotypic plasticity, but many questions remain unan- swered about how divergent plastic responses evolve under dissimilar ecological conditions. Hormones are signaling molecules that act as proximate mediators of phenotype expression by regulating a variety of cellular, physiological, and behavioral re- sponses. Hormones not only change cellular and physiological states but also influence gene expression directly or indirectly, thereby linking environmental conditions to phenotypic development. Studying how hormonal pathways respond to environ- mental variation and how those responses differ between individuals, populations, and species can expand our understanding of the evolution of phenotypic plasticity. Here, we explore the ways that the study of hormone signaling is providing new insights into the underlying proximate bases for individual, population or species variation in plasticity. Using several studies as exem- plars, we examine how a ＇norm of reaction＇ approach can be used in investigations of hormone-mediated plasticity to inform the following： 1） how environmental cues affect the component hormones, receptors and enzymes that comprise any endocrine sig- naling pathway, 2） how genetic and epigenetic variation in endocrine-associated genes can generate variation in plasticity among these diverse components, and 3） how phenotypes mediated by the same hormone can be coupled and decoupled via independent plastic responses of signaling components across target tissues. Future studies that apply approaches such as reaction norms and network modeling to questions concerning how hormones link environmental stimuli to ecologically-relevant phenotypic re- sponses should help unravel how phenotypic plasticity evolves展开更多
Morphologically divergent ecotypes arise in fish populations on postglacial time scales, and resource polymorphisms are often invoked to explain their origin. However, genetic recombination can constrain the ability o...Morphologically divergent ecotypes arise in fish populations on postglacial time scales, and resource polymorphisms are often invoked to explain their origin. However, genetic recombination can constrain the ability of divergent selection to pro- duce reproductive isolation in sympatry. Recombination breaks up favorable combinations of traits （＂adaptive suites＂） if indivi- dual traits are affected by different loci. Recombination also breaks up any association between traits under divergent selection and traits contributing to reproductive isolation. Thus, ecological speciation in the absence of preexisting barriers to gene flow is more likely when pleiotropy minimizes the number of loci involved. Here, we revisit research conducted by Carl Hubbs in the early 1900s on the effects of developmental rate on morphological traits in fishes. Hubbs＇ work provides a mechanism to explain how sympatric divergence by trophic polymorphism can occur despite the challenges of recombination. We consider the implica- tions of Hubbs＇ observations for ecological speciation with gene flow in fishes, as well as rapid evolution in captive fish popula- tions [Current Zoology 58 （1）： 21-34, 2012].展开更多
An emerging area of interest in understanding disease phenotypes is systems genomics.Complex diseases such as diabetes have played an important role towards understanding the susceptible genes and mutations.A wide num...An emerging area of interest in understanding disease phenotypes is systems genomics.Complex diseases such as diabetes have played an important role towards understanding the susceptible genes and mutations.A wide number of methods have been employed and strategies such as polygenic risk score and allele frequencies have been useful,but understanding the candidate genes harboring those mutations is an unmet goal.In this perspective,using systems genomic approaches,we highlight the application of phenome-interactome networks in diabetes and provide deep insights.LINC01128,which we previously described as candidate for diabetes,is shown as an example to discuss the approach.展开更多
This article represents the main positions of the theory of pleiotropic action of biologically active compounds (BACs) and medicines, which has been designed by the author based on her own experimental researches. The...This article represents the main positions of the theory of pleiotropic action of biologically active compounds (BACs) and medicines, which has been designed by the author based on her own experimental researches. The term “pleiotropy” means the ability of the BACs and medicines to implement more than one mechanism of action resulting in the specific biological (pharmacological) effect. The interaction of these mechanisms forms a distinct pattern of biological response (pleiotropic pattern), which reflects the change in his character with the increased dose (concentration)-dependent efficacy of BACs and medicines. The article consists of description of different pleiotropic patterns established in experiments on the model of reactive oxygen species (ROS) generation by macrophages dependent on activity of specialized enzyme called Nox2-NAD(P)H oxidase (Nox2, EC 1.6.3.1). Moreover, it consists of explanation of pharmacodynamic nature of pleiotropic patterns by means of application Chou-Talalay median effect equalization and combination index (CI) theory. The novel theory explains unsolved until now universal aspects of activity BACs and medicines, such as slope angles of “dose-effect” dependences in the conditions relevant in vivo, and it is of fundamental interest. However, it has applications in experimental pharmacology, as it allows defining the choice of the individual compounds and combinations, modulating the trust effect selectively and efficiently. This knowledge opens up new approaches to medicines discovery and evaluation, their rational dosing and combining.展开更多
Psychiatric disorders have traditionally been segregated from medical disorders in terms of drugs,treatment,insurance coverage and training of clinicians.This segregation is consistent with the long-standing observati...Psychiatric disorders have traditionally been segregated from medical disorders in terms of drugs,treatment,insurance coverage and training of clinicians.This segregation is consistent with the long-standing observation that there are inherent differences between psychiatric disorders(diseases relating to thoughts,feelings and behavior)and medical disorders(diseases relating to physical processes).However,these differences are growing less distinct as we improve our understanding of the roles of epistasis and pleiotropy in medical genetics.Both psychiatric and medical disorders are predisposed in part by genetic variation,and psychiatric disorders tend to be comorbid with medical disorders.One hypothesis on this interaction posits that certain combinations of genetic variants(epistasis)influence psychiatric disorders due to their impact on the brain,but the associated genes are also expressed in other tissues so the same groups of variants influence medical disorders(pleiotropy).The observation that psychiatric and medical disorders may interact is not novel.Equally,both epistasis and pleiotropy are fundamental concepts in medical genetics.However,we are just beginning to understand how genetic variation can influence both psychiatric and medical disorders.In our recent work,we have discovered gene networks significantly associated with psychiatric and substance use disorders.Invariably,these networks are also significantly associated with medical disorders.Recognizing how genetic variation can influence both psychiatric and medical disorders will help us to understand the etiology of the individual and comorbid disease phenotypes,predict and minimize side effects in drug and other treatments,and help to reduce stigma associated with psychiatric disorders.展开更多
Complex demographic processes and natural selection pressures are critical to resolving patterns of the molecular genetic basis of adaptive traits or complex diseases.Recent ancient genome data allow us to trace how k...Complex demographic processes and natural selection pressures are critical to resolving patterns of the molecular genetic basis of adaptive traits or complex diseases.Recent ancient genome data allow us to trace how key traits evolved in different human populations over time,connecting ancient population history with disease susceptibility in western Eurasians.To fill this gap in eastern Eurasians and provide deep insights into the evolutionary history of the populationspecific genetic basis of complex biological traits,we explored the evolutionary basis of adaptive traits in one integrative modern and ancient genomic database,including 225 out of 5583 genomes first reported here.We comprehensively characterized the demographic history and biological adaptation of Han Chinese individuals on the Mongolian Plateau based on the allele frequency spectrum and haplotype-resolved fragments.We found strong genetic homogeneity among geographically different Han populations from Inner Mongolia(IMH).We reconstructed their admixture models and demographic events,revealing that IMH had a close genetic relationship with ancient millet farmers and obtained additional gene flow from Altaic-speaking populations.The enrichment of selected candidate genes suggested that essential metabolism-related genes promoted the rapid adaptation of eastern Eurasians to ancient environmental shifts and dietary changes during agricultural innovations.Evolutionary trajectory reconstruction of metabolism-related genes of methylenetetrahydrofolate reductase(MTHFR)and fatty acid desaturase 1(FADS1)suggested that ancient dietary shifts during the Neolithic transition period promoted the differentiated metabolic rate of folate and fatty acid.We revealed the polygenicity of biological adaptation traits and the pleiotropy of adaptive genes,indicating that complex recent polygenic adaptations,genetic interactions,and genotype–phenotype correlations have contributed to the genetic architecture of complex traits in eastern Eurasians.展开更多
Mendelian randomisation is an accessible and valuable epidemiological approach to provide insight into the causal nature of relationships between risk factor exposures and disease outcomes.However,if performed without...Mendelian randomisation is an accessible and valuable epidemiological approach to provide insight into the causal nature of relationships between risk factor exposures and disease outcomes.However,if performed without critical thought,we may simply have replaced one set of implausible assumptions(no unmeasured confounding or reverse causation)with another set of implausible assumptions(no pleiotropy or other instrument invalidity).The most critical decision to avoid pleiotropy is which genetic variants to use as instrumental variables.Two broad strategies for instrument selection are a biologically motivated strategy and a genome-wide strategy;in general,a biologically motivated strategy is preferred.In this review,we discuss various ways of implementing a biologically motivated selection strategy:using variants in a coding gene region for the exposure or a gene region that encodes a regulator of exposure levels,using a positive control variable and using a biomarker as the exposure rather than its behavioural proxy.In some cases,a genome-wide analysis can provide important complementary evidence,even when its reliability is questionable.In other cases,a biologically-motivated analysis may not be possible.The choice of genetic variants must be informed by biological and functional considerations where possible,requiring collaboration to combine biological and clinical insights with appropriate statistical methodology.展开更多
Although many susceptibility loci for IgA nephropathy(IgAN)have been identified,they only account for 11.0%of the overall IgAN variance.We performed a large genome-wide meta-analysis of IgAN in Han Chinese with 3616 c...Although many susceptibility loci for IgA nephropathy(IgAN)have been identified,they only account for 11.0%of the overall IgAN variance.We performed a large genome-wide meta-analysis of IgAN in Han Chinese with 3616 cases and 10417 controls to identify additional genetic loci of IgAN.Considering that inflammatory bowel disease(IBD)and asthma might share an etiology of dysregulated mucosal immunity with IgAN,we performed cross-trait integrative analysis by leveraging functional annotations of relevant cell type and the pleiotropic information from IBD and asthma.Among 8669456 imputed variants,we identified a novel locus at 4p14 containing the long noncoding RNA LOC101060498.Cell type enrichment analysis based on annotations suggested that PMA-I-stimulated CD4+CD25–IL17+Th17 cell was the most relevant cell type for IgAN,which highlights the essential role of Th17 pathway in the pathogenesis of IgAN.Furthermore,we identified six more novel loci associated with IgAN,which included three loci showing pleiotropic effects with IBD or asthma(2q35/PNKD,6q25.2/SCAF8,and 22q11.21/UBE2L3)and three loci specific to IgAN(14q32.32/TRAF3,16q22.2/TXNL4B,and 21q21.3/LINC00113)in the pleiotropic analysis.Our findings support the involvement of mucosal immunity,especially T cell immune response and IL-17 signal pathway,in the development of IgAN and shed light on further investigation of IgAN.展开更多
The semi-determinate stem growth habit in leguminous crops,similar to the“green revolution”semi-dwarf trait in cereals,is a key plant architecture trait that affects several other traits determining grain yield.In s...The semi-determinate stem growth habit in leguminous crops,similar to the“green revolution”semi-dwarf trait in cereals,is a key plant architecture trait that affects several other traits determining grain yield.In soybean semi-determinacy is modulated by a post-domestication gain-of-function mutation in the gene,Dt2,which encodes an MADS-box transcription factor.However,its role in systemic modification of stem growth and other traits is unknown.In this study,we show that Dt2 functions not only as a direct repressor of Dt1,which prevents terminal flowering,but also as a direct activator of putative floral integrator/identity genes including GmSOC1,GmAP1,and GmFUL,which likely promote flowering.We also demonstrate that Dt2 functions as a direct repressor of the putative drought-responsive transcription factor gene GmDREB1D,and as a direct activator of GmSPCH and GmGRP7,which are potentially associated with asymmetric division of young epidermal cells and stomatal opening,respectively,and may affect the plant's water-use efficiency(WUE).Intriguingly,Dt2 was found to be a direct activator or repressor of the precursors of eight microRNAs targeting genes potentially associated with meristem maintenance,flowering time,stomatal density,WUE,and/or stress responses.This study thus reveals the molecular basis of pleiotropy associated with plant productivity,adaptability,and environmental resilience.展开更多
The clinical diagnosis of neurodegenerative disorders based on phenotype is difficult in heterogeneous conditions with overlapping symptoms.It does not take into account the disease etiology or the highly variable cli...The clinical diagnosis of neurodegenerative disorders based on phenotype is difficult in heterogeneous conditions with overlapping symptoms.It does not take into account the disease etiology or the highly variable clinical course even amongst patients diagnosed with the same disorder.The advent of next generation sequencing(NGS)has allowed for a system-wide,unbiased approach to identify all gene variants in the genome simultaneously.With the plethora of new genes being identified,genetic rather than phenotype-based classification of Mendelian diseases such as spinocerebellar ataxia(SCA),hereditary spastic paraplegia(HSP)and Charcot-Marie-Tooth disease(CMT)has become widely accepted.It has also become clear that gene variants play a role in common and predominantly sporadic neurodegenerative diseases such as Parkinson’s disease(PD)and amyotrophic lateral sclerosis(ALS).The observation of pleiotropy has emerged,with mutations in the same gene giving rise to diverse phenotypes,which further increases the complexity of phenotype-genotype correlation.Possible mechanisms of pleiotropy include different downstream effects of different mutations in the same gene,presence of modifier genes,and oligogenic inheritance.Future directions include development of bioinformatics tools and establishment of more extensive public genotype/phenotype databases to better distinguish deleterious gene variants from benign polymorphisms,translation of genetic findings into pathogenic mechanisms through in-vitro and in-vivo studies,and ultimately finding disease-modifying therapies for neurodegenerative disorders.展开更多
Base editing technology is being increasingly applied in genome engineering,but the current strategy for designing guide RNAs(gRNAs)relies substantially on empirical experience rather than a dependable and efficient i...Base editing technology is being increasingly applied in genome engineering,but the current strategy for designing guide RNAs(gRNAs)relies substantially on empirical experience rather than a dependable and efficient in silico design.Furthermore,the pleiotropic effect of base editing on disease treatment remains unexplored,which prevents its further clinical usage.Here,we presented BExplorer,an integrated and comprehensive computational pipeline to optimize the design of gRNAs for 26 existing types of base editors in silico.Using BExplorer,we described its results for two types of mainstream base editors,BE3 and ABE7.10,and evaluated the pleiotropic effects of the corresponding base editing loci.BExplorer revealed 524 and 900 editable pathogenic single nucleotide polymorphism(SNP)loci in the human genome together with the selected optimized gRNAs for BE3 and ABE7.10,respectively.In addition,the impact of 707 edited pathogenic SNP loci following base editing on 131 diseases was systematically explored by revealing their pleiotropic effects,indicating that base editing should be carefully utilized given the potential pleiotropic effects.Collectively,the systematic exploration of optimized base editing gRNA design and the corresponding pleiotropic effects with BExplorer provides a computational basis for applying base editing in disease treatment.展开更多
The developmental origins of health and disease theory states that environmental stresses during the early stages of life influence health and risk of developing non-communicable diseases throughout the lifespan of an...The developmental origins of health and disease theory states that environmental stresses during the early stages of life influence health and risk of developing non-communicable diseases throughout the lifespan of an individual.Developmental plasticity is thought to be a possible underlying mechanism.Here,I discuss a contrasting but complementary genetic hypothesis regarding the developmental origins of health and disease theory:crosstalk between the genomes of the parents and offspring is responsible for shaping and adapting responses to environmental stresses,regulating early growth and predisposition to non-communicable diseases.Genetic variants that are beneficial in terms of responses to early life stresses may have pleiotropic detrimental effects on health later in life,which may change the allele frequencies driven by selection on a population level.Genetic studies on the cohort of children born after assisted reproduction could provide insight regarding the genetic mechanisms of the developmental origins of health and disease theory.展开更多
基金supported by National Key Research and Development Program of China under Grant No.2017YFA0604903the National Natural Science Foundation of China under Grant No.11971064the Ph.D.start-up fund of Hubei University of Science and Technology under Grant No.BK201813。
文摘To test genetic pleiotropy,the main difficulty lies in the failure to find a test statistic and calculate its p-value for determining whether to reject the null hypothesis or not.To deal with this issue,the authors propose a quasi p-value,which plays the similar role as the usual p-value in genetic pleiotropy test.In the formula of the quasi p-value,the main task is to determine the weights.In this paper,the authors present two weighted methods based on the Bayesian rule and extend the proposed methods to study a single binary trait using a data-driven EM algorithm.Extensive simulation studies are conducted for the assessment of the two proposed methods and illustrate that the proposed methods improve the performance of power by comparing with the two-stage method.In addition,the authors apply the proposed methods to the data of tropical storms that occurred on the mainland of China since 1949,investigating the relationship between the landing site and predictive features of tropical storms,and showing that the landing site has a large influence on at least two features of typhoon.
基金Supported by Guangxi Training Program for Medical High-level Academic LeadersBose Talent Highland+3 种基金Building Projects of Guangxi Bagui Scholars,No.Guirencaiban[2024]-39Building Projects from the Key Laboratory of Molecular Pathology(Hepatobiliary Diseases)of Guangxi,the Key Laboratory of Tumor Molecular Pathology of Guangxi Colleges&UniversitiesClinical Key Specialty Building Project(For Pathology)of Guangxiand Nanshan District Health System Science and Technology Major Project,No.NSZD2024045.
文摘We reviewed the study by He et al,which investigates the genetic correlation between ulcerative colitis(UC)and anxiety using bidirectional Mendelian rando-mization.This study reveals a genetic link between UC and anxiety,diverging from prior research associating higher anxiety with Crohn’s disease.While the study's use of large-scale genome-wide association studies data is commendable,it faces limitations such as single nucleotide polymorphism selection biases,lack of multiple testing corrections,and a reliance on European populations.Future research should address these limitations,incorporate diverse populations,and explore psychotherapeutic interventions to improve UC management and patient outcomes.
基金partially supported by the Science and Technology Innovation Program of Hunan Province,China(2023NK2001)the Hubei Key Laboratory of Food Crop Germplasm and Genetic Improvement,China(2022LZJJ08)+2 种基金the Special Funds for Construction of Innovative Provinces in Hunan Province,China(2021NK1011)the Natural Science Foundation of Hunan Province,China(2020JJ4039)the Key Research and Development Program of Hubei Province,China(2021BBA223)。
文摘Marker-assisted selection(MAS)and genomic selection(GS)breeding have greatly improved the efficiency of rice breeding.Due to the influences of epistasis and gene pleiotropy,ensuring the actual breeding effect of MAS and GS is still a difficult challenge to overcome.In this study,113 indica rice varieties(V)and their 565 testcross hybrids(TC)were used as the materials to investigate the genetic basis of 12 quality traits and nine agronomic traits.The original traits and general combining ability of the parents,as well as the original traits and midparent heterosis of TC,were subjected to genome-wide association analysis.In total,381 primary significantly associated loci(SAL)and 1,759 secondary SALs that had epistatic interactions with these primary SALs were detected.Among these loci,322 candidate genes located within or nearby the SALs were screened,204 of which were cloned genes.A total of 39 MAS molecular modules that are beneficial for trait improvement were identified by pyramiding the superior haplotypes of candidate genes and desirable epistatic alleles of the secondary SALs.All the SALs were used to construct genetic networks,in which 91 pleiotropic loci were investigated.Additionally,we estimated the accuracy of genomic prediction in the parent V and TC by incorporating either no SALs,primary SALs,secondary SALs or epistatic effect SALs as covariates.Although the prediction accuracies of the four models were generally not significantly different in the TC dataset,the incorporation of primary SALs,secondary SALs,and epistatic effect SALs significantly improved the prediction accuracies of 5(26%),3(16%),and 11(58%)traits in the V dataset,respectively.These results suggested that SALs and epistatic effect SALs identified based on an additive genotype can provide considerable predictive power for the parental lines.They also provide insights into the genetic basis of complex traits and valuable information for molecular breeding in rice.
基金financially supported by the Key Project of Beijing Municipal Science & Technology Commission (D16110500060000)the National Key Technology R&D Program of China (2014BAD01B09)
文摘Control of flowering time is crucial for reproductive success of cereal crops, and has a significant impact on grain yield as well as adaptation to diverse environmental conditions.Plants integrate signals from both environmental cues and endogenous regulatory pathways to fine-tune flowering time. The CCT domain originally described to a 43-amino acid sequence at the C-terminus of three Arabidopsis proteins, namely CONSTANS(CO),CO-LIKE, and TIMING OF CAB1(TOC1). The CCT domain-containing genes(CCT genes),which encode transcription co-factors, are the major genetic determinants that modulate flowering time, and this in turn enables plants to effectively expand their territory to take advantage of favorable habitats. Moreover, certain CCT genes have pleiotropic effects on morphological traits and confer resistance/tolerance to biotic/abiotic stresses. CCT genes can be classified into three families, namely COL(CONSTANS-like), PRR(Pseudo-response regulator), and CMF(CCT motif family),based on their non-CCT domains. During domestication, natural and artificial selection resulted in reduced nucleotide diversity of CCT genes in modern cultivated cereals than their wild types. Here, we review the features and functions of CCT genes in cereal crops and propose future research to focus on CCT genes and their utilization in crop breeding.
文摘Genetic factors play an important role in the etiology of inflammatory bowel disease(IBD). The launch of genome-wide association study(GWAS) represents a landmark in the genetic study of human complex disease. Concurrently, computational methods have undergone rapid development during the past a few years, which led to the identification of numerous disease susceptibility loci. IBD is one of the successful examples of GWAS and related analyses. A total of 163 genetic loci and multiple signaling pathways have been identified to be associated with IBD. Pleiotropic effects were found for many of these loci; and risk prediction models were built based on a broad spectrum of genetic variants. Important gene-gene, gene-environment interactions and key contributions of gut microbiome are being discovered. Here we will review the different types of analyses that have been applied to IBD genetic study, discuss the computational methods for each type of analysis, and summarize the discoveries made in IBD research with the application of these methods.
文摘Cascade speciation and reinforcement can evolve rapidly when traits are pleiotropic and act as both signal/cue in nonrandom mating. Here, we examine the contribution of two key traits-assortative mating and self-fertilization--to reinforcement and （by extension） cascade speciation. First, using a population genetic model of reinforcement we find that both assortative mating and self-fertilization can make independent contributions to increased reproductive isolation, consistent with reinforcement. Self-fertilization primarily evolves due to its 2-fold transmission advantage when inbreeding depression （d） is lower （d〈 0.45） but evolves as a function of the cost of hybridization under higher inbreeding depression （0.45 〈 d〈 0.48）. When both traits can evolve simultaneously, increased self-fertilization often prohibits the evolution of assortative mating. We infer that, under specific conditions, mating system transitions are more likely to lead to increased reproductive isolation and initiate cascade speciation, than assortative mating. Based on the results of our simulations, we hypothesized that transitions to self-fertilization could contribute to clade-wide diversification if reinforcement or cascade speciation is common. We tested this hypothesis with comparative data from two different groups. Consistent with our hypothesis, there was a trend towards uniparental reproduction being associated with increased diversification rate in the Nematode phylum. For the plant genus Mimulus, however, self-fertilization was associated with reduced diversification. Reinforcement driving speciation via transitions to self-fertilization might be short lived or unsustainable across macroevolutionary scales in some systems （some plants）, but not others （such as nematodes）, potentially due to differences in susceptibility to inbreeding depression and/or the ability to transition between reproductive modes.
文摘It is generally accepted that taxa exhibit genetic variation in phenotypic plasticity, but many questions remain unan- swered about how divergent plastic responses evolve under dissimilar ecological conditions. Hormones are signaling molecules that act as proximate mediators of phenotype expression by regulating a variety of cellular, physiological, and behavioral re- sponses. Hormones not only change cellular and physiological states but also influence gene expression directly or indirectly, thereby linking environmental conditions to phenotypic development. Studying how hormonal pathways respond to environ- mental variation and how those responses differ between individuals, populations, and species can expand our understanding of the evolution of phenotypic plasticity. Here, we explore the ways that the study of hormone signaling is providing new insights into the underlying proximate bases for individual, population or species variation in plasticity. Using several studies as exem- plars, we examine how a ＇norm of reaction＇ approach can be used in investigations of hormone-mediated plasticity to inform the following： 1） how environmental cues affect the component hormones, receptors and enzymes that comprise any endocrine sig- naling pathway, 2） how genetic and epigenetic variation in endocrine-associated genes can generate variation in plasticity among these diverse components, and 3） how phenotypes mediated by the same hormone can be coupled and decoupled via independent plastic responses of signaling components across target tissues. Future studies that apply approaches such as reaction norms and network modeling to questions concerning how hormones link environmental stimuli to ecologically-relevant phenotypic re- sponses should help unravel how phenotypic plasticity evolves
文摘Morphologically divergent ecotypes arise in fish populations on postglacial time scales, and resource polymorphisms are often invoked to explain their origin. However, genetic recombination can constrain the ability of divergent selection to pro- duce reproductive isolation in sympatry. Recombination breaks up favorable combinations of traits （＂adaptive suites＂） if indivi- dual traits are affected by different loci. Recombination also breaks up any association between traits under divergent selection and traits contributing to reproductive isolation. Thus, ecological speciation in the absence of preexisting barriers to gene flow is more likely when pleiotropy minimizes the number of loci involved. Here, we revisit research conducted by Carl Hubbs in the early 1900s on the effects of developmental rate on morphological traits in fishes. Hubbs＇ work provides a mechanism to explain how sympatric divergence by trophic polymorphism can occur despite the challenges of recombination. We consider the implica- tions of Hubbs＇ observations for ecological speciation with gene flow in fishes, as well as rapid evolution in captive fish popula- tions [Current Zoology 58 （1）： 21-34, 2012].
文摘An emerging area of interest in understanding disease phenotypes is systems genomics.Complex diseases such as diabetes have played an important role towards understanding the susceptible genes and mutations.A wide number of methods have been employed and strategies such as polygenic risk score and allele frequencies have been useful,but understanding the candidate genes harboring those mutations is an unmet goal.In this perspective,using systems genomic approaches,we highlight the application of phenome-interactome networks in diabetes and provide deep insights.LINC01128,which we previously described as candidate for diabetes,is shown as an example to discuss the approach.
文摘This article represents the main positions of the theory of pleiotropic action of biologically active compounds (BACs) and medicines, which has been designed by the author based on her own experimental researches. The term “pleiotropy” means the ability of the BACs and medicines to implement more than one mechanism of action resulting in the specific biological (pharmacological) effect. The interaction of these mechanisms forms a distinct pattern of biological response (pleiotropic pattern), which reflects the change in his character with the increased dose (concentration)-dependent efficacy of BACs and medicines. The article consists of description of different pleiotropic patterns established in experiments on the model of reactive oxygen species (ROS) generation by macrophages dependent on activity of specialized enzyme called Nox2-NAD(P)H oxidase (Nox2, EC 1.6.3.1). Moreover, it consists of explanation of pharmacodynamic nature of pleiotropic patterns by means of application Chou-Talalay median effect equalization and combination index (CI) theory. The novel theory explains unsolved until now universal aspects of activity BACs and medicines, such as slope angles of “dose-effect” dependences in the conditions relevant in vivo, and it is of fundamental interest. However, it has applications in experimental pharmacology, as it allows defining the choice of the individual compounds and combinations, modulating the trust effect selectively and efficiently. This knowledge opens up new approaches to medicines discovery and evaluation, their rational dosing and combining.
文摘Psychiatric disorders have traditionally been segregated from medical disorders in terms of drugs,treatment,insurance coverage and training of clinicians.This segregation is consistent with the long-standing observation that there are inherent differences between psychiatric disorders(diseases relating to thoughts,feelings and behavior)and medical disorders(diseases relating to physical processes).However,these differences are growing less distinct as we improve our understanding of the roles of epistasis and pleiotropy in medical genetics.Both psychiatric and medical disorders are predisposed in part by genetic variation,and psychiatric disorders tend to be comorbid with medical disorders.One hypothesis on this interaction posits that certain combinations of genetic variants(epistasis)influence psychiatric disorders due to their impact on the brain,but the associated genes are also expressed in other tissues so the same groups of variants influence medical disorders(pleiotropy).The observation that psychiatric and medical disorders may interact is not novel.Equally,both epistasis and pleiotropy are fundamental concepts in medical genetics.However,we are just beginning to understand how genetic variation can influence both psychiatric and medical disorders.In our recent work,we have discovered gene networks significantly associated with psychiatric and substance use disorders.Invariably,these networks are also significantly associated with medical disorders.Recognizing how genetic variation can influence both psychiatric and medical disorders will help us to understand the etiology of the individual and comorbid disease phenotypes,predict and minimize side effects in drug and other treatments,and help to reduce stigma associated with psychiatric disorders.
基金We thank all the volunteers who participated in this project and the researchers who provided help and support for this project(Prof.Etienne Patin and Prof.Lluis Quintana-Murci from the Human Evolutionary Genetics Unit of the Institute PasteurProf.Mark Stoneking and Prof.Dang Liu from the Max Planck Institute for Evolutionary Anthropology+5 种基金and Prof.Wibhu Kutanan from Khon Kaen University).We are indebted to Grammarly(https://app.grammarly.com/)for its invaluable contribution to the linguistic refinement and readability enhancement of this manuscript.M.W.is supported by the National Natural Science Foundation of China(82202078)G.H.is supported by the Major Project of the National Social Science Foundation of China(23&ZD203)the Open Project of the Key Laboratory of Forensic Genetics of the Ministry of Public Security(2022FGKFKT05)the Center for Archaeological Science of Sichuan University(23SASA01)the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC20002)the Sichuan Science and Technology Program.L.H.is supported by the Open Project of Shanghai Key Laboratory of Forensic Medicine(KF202309).
文摘Complex demographic processes and natural selection pressures are critical to resolving patterns of the molecular genetic basis of adaptive traits or complex diseases.Recent ancient genome data allow us to trace how key traits evolved in different human populations over time,connecting ancient population history with disease susceptibility in western Eurasians.To fill this gap in eastern Eurasians and provide deep insights into the evolutionary history of the populationspecific genetic basis of complex biological traits,we explored the evolutionary basis of adaptive traits in one integrative modern and ancient genomic database,including 225 out of 5583 genomes first reported here.We comprehensively characterized the demographic history and biological adaptation of Han Chinese individuals on the Mongolian Plateau based on the allele frequency spectrum and haplotype-resolved fragments.We found strong genetic homogeneity among geographically different Han populations from Inner Mongolia(IMH).We reconstructed their admixture models and demographic events,revealing that IMH had a close genetic relationship with ancient millet farmers and obtained additional gene flow from Altaic-speaking populations.The enrichment of selected candidate genes suggested that essential metabolism-related genes promoted the rapid adaptation of eastern Eurasians to ancient environmental shifts and dietary changes during agricultural innovations.Evolutionary trajectory reconstruction of metabolism-related genes of methylenetetrahydrofolate reductase(MTHFR)and fatty acid desaturase 1(FADS1)suggested that ancient dietary shifts during the Neolithic transition period promoted the differentiated metabolic rate of folate and fatty acid.We revealed the polygenicity of biological adaptation traits and the pleiotropy of adaptive genes,indicating that complex recent polygenic adaptations,genetic interactions,and genotype–phenotype correlations have contributed to the genetic architecture of complex traits in eastern Eurasians.
基金SB is supported by the Wellcome Trust(225790/Z/22/Z)the United Kingdom Research and Innovation Medical Research Council(MC_UU_00002/7)This research was supported by the National Institute for Health Research Cambridge Biomedical Research Centre(NIHR203312).
文摘Mendelian randomisation is an accessible and valuable epidemiological approach to provide insight into the causal nature of relationships between risk factor exposures and disease outcomes.However,if performed without critical thought,we may simply have replaced one set of implausible assumptions(no unmeasured confounding or reverse causation)with another set of implausible assumptions(no pleiotropy or other instrument invalidity).The most critical decision to avoid pleiotropy is which genetic variants to use as instrumental variables.Two broad strategies for instrument selection are a biologically motivated strategy and a genome-wide strategy;in general,a biologically motivated strategy is preferred.In this review,we discuss various ways of implementing a biologically motivated selection strategy:using variants in a coding gene region for the exposure or a gene region that encodes a regulator of exposure levels,using a positive control variable and using a biomarker as the exposure rather than its behavioural proxy.In some cases,a genome-wide analysis can provide important complementary evidence,even when its reliability is questionable.In other cases,a biologically-motivated analysis may not be possible.The choice of genetic variants must be informed by biological and functional considerations where possible,requiring collaboration to combine biological and clinical insights with appropriate statistical methodology.
基金supported by Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases(No.2019B121205005)National Natural Science Foundation of China(Nos.81920108008,81770661,82170714,and 82003561)+2 种基金Guangzhou Municipal Science and Technology Project of China(No.202201011246)Basic and Applied Basic Research Foundation of Guangdong Province(No.2021A1515111054)Fundamental Research Funds for the Central Universities(No.2019kfyXJJS036).
文摘Although many susceptibility loci for IgA nephropathy(IgAN)have been identified,they only account for 11.0%of the overall IgAN variance.We performed a large genome-wide meta-analysis of IgAN in Han Chinese with 3616 cases and 10417 controls to identify additional genetic loci of IgAN.Considering that inflammatory bowel disease(IBD)and asthma might share an etiology of dysregulated mucosal immunity with IgAN,we performed cross-trait integrative analysis by leveraging functional annotations of relevant cell type and the pleiotropic information from IBD and asthma.Among 8669456 imputed variants,we identified a novel locus at 4p14 containing the long noncoding RNA LOC101060498.Cell type enrichment analysis based on annotations suggested that PMA-I-stimulated CD4+CD25–IL17+Th17 cell was the most relevant cell type for IgAN,which highlights the essential role of Th17 pathway in the pathogenesis of IgAN.Furthermore,we identified six more novel loci associated with IgAN,which included three loci showing pleiotropic effects with IBD or asthma(2q35/PNKD,6q25.2/SCAF8,and 22q11.21/UBE2L3)and three loci specific to IgAN(14q32.32/TRAF3,16q22.2/TXNL4B,and 21q21.3/LINC00113)in the pleiotropic analysis.Our findings support the involvement of mucosal immunity,especially T cell immune response and IL-17 signal pathway,in the development of IgAN and shed light on further investigation of IgAN.
文摘The semi-determinate stem growth habit in leguminous crops,similar to the“green revolution”semi-dwarf trait in cereals,is a key plant architecture trait that affects several other traits determining grain yield.In soybean semi-determinacy is modulated by a post-domestication gain-of-function mutation in the gene,Dt2,which encodes an MADS-box transcription factor.However,its role in systemic modification of stem growth and other traits is unknown.In this study,we show that Dt2 functions not only as a direct repressor of Dt1,which prevents terminal flowering,but also as a direct activator of putative floral integrator/identity genes including GmSOC1,GmAP1,and GmFUL,which likely promote flowering.We also demonstrate that Dt2 functions as a direct repressor of the putative drought-responsive transcription factor gene GmDREB1D,and as a direct activator of GmSPCH and GmGRP7,which are potentially associated with asymmetric division of young epidermal cells and stomatal opening,respectively,and may affect the plant's water-use efficiency(WUE).Intriguingly,Dt2 was found to be a direct activator or repressor of the precursors of eight microRNAs targeting genes potentially associated with meristem maintenance,flowering time,stomatal density,WUE,and/or stress responses.This study thus reveals the molecular basis of pleiotropy associated with plant productivity,adaptability,and environmental resilience.
文摘The clinical diagnosis of neurodegenerative disorders based on phenotype is difficult in heterogeneous conditions with overlapping symptoms.It does not take into account the disease etiology or the highly variable clinical course even amongst patients diagnosed with the same disorder.The advent of next generation sequencing(NGS)has allowed for a system-wide,unbiased approach to identify all gene variants in the genome simultaneously.With the plethora of new genes being identified,genetic rather than phenotype-based classification of Mendelian diseases such as spinocerebellar ataxia(SCA),hereditary spastic paraplegia(HSP)and Charcot-Marie-Tooth disease(CMT)has become widely accepted.It has also become clear that gene variants play a role in common and predominantly sporadic neurodegenerative diseases such as Parkinson’s disease(PD)and amyotrophic lateral sclerosis(ALS).The observation of pleiotropy has emerged,with mutations in the same gene giving rise to diverse phenotypes,which further increases the complexity of phenotype-genotype correlation.Possible mechanisms of pleiotropy include different downstream effects of different mutations in the same gene,presence of modifier genes,and oligogenic inheritance.Future directions include development of bioinformatics tools and establishment of more extensive public genotype/phenotype databases to better distinguish deleterious gene variants from benign polymorphisms,translation of genetic findings into pathogenic mechanisms through in-vitro and in-vivo studies,and ultimately finding disease-modifying therapies for neurodegenerative disorders.
基金supported by the National Key R&D Program of China(Grant No.2021YFF1201200)the National Natural Science Foundation of China(Grant Nos.31970638 and 61572361)+2 种基金the Shanghai Natural Science Foundation Program(Grant No.17ZR1449400)the Shanghai Artificial Intelligence Technology Standard Project(Grant No.19DZ2200900)the Shanghai Shuguang scholars project,the WeBank scholars project,and the Fundamental Research Funds for the Central Universities.
文摘Base editing technology is being increasingly applied in genome engineering,but the current strategy for designing guide RNAs(gRNAs)relies substantially on empirical experience rather than a dependable and efficient in silico design.Furthermore,the pleiotropic effect of base editing on disease treatment remains unexplored,which prevents its further clinical usage.Here,we presented BExplorer,an integrated and comprehensive computational pipeline to optimize the design of gRNAs for 26 existing types of base editors in silico.Using BExplorer,we described its results for two types of mainstream base editors,BE3 and ABE7.10,and evaluated the pleiotropic effects of the corresponding base editing loci.BExplorer revealed 524 and 900 editable pathogenic single nucleotide polymorphism(SNP)loci in the human genome together with the selected optimized gRNAs for BE3 and ABE7.10,respectively.In addition,the impact of 707 edited pathogenic SNP loci following base editing on 131 diseases was systematically explored by revealing their pleiotropic effects,indicating that base editing should be carefully utilized given the potential pleiotropic effects.Collectively,the systematic exploration of optimized base editing gRNA design and the corresponding pleiotropic effects with BExplorer provides a computational basis for applying base editing in disease treatment.
文摘The developmental origins of health and disease theory states that environmental stresses during the early stages of life influence health and risk of developing non-communicable diseases throughout the lifespan of an individual.Developmental plasticity is thought to be a possible underlying mechanism.Here,I discuss a contrasting but complementary genetic hypothesis regarding the developmental origins of health and disease theory:crosstalk between the genomes of the parents and offspring is responsible for shaping and adapting responses to environmental stresses,regulating early growth and predisposition to non-communicable diseases.Genetic variants that are beneficial in terms of responses to early life stresses may have pleiotropic detrimental effects on health later in life,which may change the allele frequencies driven by selection on a population level.Genetic studies on the cohort of children born after assisted reproduction could provide insight regarding the genetic mechanisms of the developmental origins of health and disease theory.
